Summary of Work: : Components of the inflammatory pathways have been demonstrated to play a significant role in the initiation, progression and maturation of atherosclerotic plaques in animal and human studies. The deposition of macrophages in arterial vessel walls as a result of endothelial injury following exposure to the major risk factors for stroke, such as hypertension, diabetes, hypercholesterolemia, and smoking, lead to a potential pro-inflammatory tissue which can result in increased intravascular thrombosis at the site of plaque formation resulting in heart attack and stroke. However, despite the presence of these prerequisite vascular changes, not all atherosclerotic plaques result in thrombotic or thromboembolic events and the overall morphologic and cellular characteristics have been inconsistent indices for predicting plaque conversion to a symptomatic or pro-thrombotic state. We have hypothesized that inflammatory processes within the body of the plaque are pivotal in the conversion of the overlying endothelium to a pro-inflammatory and pro-thrombotic state. We further hypothesized that those patients who are symptomatic exhibit a pro- inflammatory profile in a measurable fashion both at the endothelial surface of the plaque and in the peripheral blood as compared to those patients who are asymptomatic. Studies in our labs thus far have demonstrated a greater than twofold increase in intercellular adhesion molecule-1 (ICAM-1) expression on the endothelial surface of plaques from patients who are symptomatic versus those who are asymptomatic. Those patients also display an increase in soluble ICAM-1 in the peripheral blood as well as an upregulation of a cell surface adhesion molecule MAC-1 on circulating monocytes. Given the mounting evidence for the pro-inflammatory profile in patients who have symptomatic atherothrombotic disease, we further hypothesize that the inflammatory response is in part a function of genetic profile. Preliminary studies in our patients reveal an increased frequency in a known polymorphism in the promoter region of the TNF-a gene in patients who develop atherosclerotic disease versus those who are free of plaque formation. Current studies will further test the hypothesis that gene polymorphisms that enhance the pro-inflammatory state increases patients susceptibility to the development of atherosclerosis and atherothrombotic events. The cascade of events that follows cerebral ischemia is a dynamic interplay among the various cells in the region of damaged tissue that include neurons, astrocytes, fibroblasts, smooth muscle cells, and endothelial cells as well as blood components. In addition to excitatory neuro-toxicity, a growing body of evidence indicates that inflammatory mechanisms and components of the immune system are activated and believed to significantly contribute to secondary neuronal injury in the setting of acute stroke. We hypothesize that a measurable inflammatory response correlates with the severity of tissue injury. Initial studies in our labs reveal an elevation of both pro- and anti-inflammatory cytokines in the peripheral blood in the first 24 to 72 hours following an infarct. Expression of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and neopterin was noted in the first three days following ischemia despite the lack of measurable TNF-alpha and IL-1beta in the peripheral blood. Future studies are designed to expand this data to establish consistent and reliable markers for the activation of the inflammatory pathways that can be used to monitor the effects of interventional agents in acute stroke. - Atherosclerosis, Stroke, Cytokines, Inflammation, Polymorphisms - Human Subjects